Conrad F. Shamlaye

Prenatal methylmercury exposure from ocean fish consumption in the Seychelles child development study

INTRODUCTION Exposure to methylmercury (MeHg) before birth can adversely affect childrens neurodevelopment. The most common form of prenatal exposure is maternal fish consumption, but whether such exposure harms the fetus is unknown. We aimed to identify adverse neurodevelopmental effects in a fish-consuming population. METHODS We investigated 779 mother-infant pairs residing in the Republic of Seychelles. Mothers reported consuming fish on average 12 meals per week. Fish in Seychelles contain much the same concentrations of MeHg as commercial ocean fish elsewhere. Prenatal MeHg exposure was determined from maternal hair growing during pregnancy. We assessed neurocognitive, language, memory, motor, perceptual-motor, and behavioural functions in children at age 9 years. The association between prenatal MeHg exposure and the primary endpoints was investigated with multiple linear regression with adjustment for covariates that affect child development. FINDINGS Mean prenatal MeHg exposure was 6.9 parts per million (SD 4.5 ppm). Only two endpoints were associated with prenatal MeHg exposure. Increased exposure was associated with decreased performance in the grooved pegboard using the non-dominant hand in males and improved scores in the hyperactivity index of the Conners teacher rating scale. Covariates affecting child development were appropriately associated with endpoints. INTERPRETATION These data do not support the hypothesis that there is a neurodevelopmental risk from prenatal MeHg exposure resulting solely from ocean fish consumption.

Plasma Aldosterone Is Independently Associated With the Metabolic Syndrome

The aim of this study was to analyze the associations of plasma aldosterone and plasma renin activity with the metabolic syndrome and each of its components. We analyzed data from a family based study in the Seychelles made up of 356 participants (160 men and 196 women) from 69 families of African descent. In multivariable models, plasma aldosterone was associated positively (P<0.05) with blood pressure in older individuals (interaction with age, P<0.05) and with waist circumference in men (interaction with sex, P<0.05) and negatively with high-density lipoprotein cholesterol, in particular in individuals with elevated urinary potassium excretion (interaction with urinary potassium, P<0.05); plasma renin activity was significantly associated with triglycerides and fasting blood glucose. Plasma aldosterone, but not plasma renin activity, was associated with the metabolic syndrome per se, independently of the association with its separate components. The observation that plasma renin activity was associated with some components of the metabolic syndrome, whereas plasma aldosterone was associated with other components of the metabolic syndrome, suggests different underlying mechanisms. These findings reinforce previous observations suggesting that aldosterone is associated with several cardiovascular risk factors and also suggest that aldosterone might contribute to the increased cardiovascular disease risk in individuals of African descent with the metabolic syndrome.

Associations of maternal long-chain polyunsaturated fatty acids, methyl mercury, and infant development in the Seychelles Child Development Nutrition Study.

Fish consumption during gestation can provide the fetus with long-chain polyunsaturated fatty acids (LCPUFA) and other nutrients essential for growth and development of the brain. However, fish consumption also exposes the fetus to the neurotoxicant, methyl mercury (MeHg). We studied the association between these fetal exposures and early child development in the Seychelles Child Development Nutrition Study (SCDNS). Specifically, we examined a priori models of Omega-3 and Omega-6 LCPUFA measures in maternal serum to test the hypothesis that these LCPUFA families before or after adjusting for prenatal MeHg exposure would reveal associations with child development assessed by the BSID-II at ages 9 and 30 months. There were 229 children with complete outcome and covariate data available for analysis. At 9 months, the PDI was positively associated with total Omega-3 LCPUFA and negatively associated with the ratio of Omega-6/Omega-3 LCPUFA. These associations were stronger in models adjusted for prenatal MeHg exposure. Secondary models suggested that the MeHg effect at 9 months varied by the ratio of Omega-6/Omega-3 LCPUFA. There were no significant associations between LCPUFA measures and the PDI at 30 months. There were significant adverse associations, however, between prenatal MeHg and the 30-month PDI when the LCPUFA measures were included in the regression analysis. The BSID-II mental developmental index (MDI) was not associated with any exposure variable. These data support the potential importance to child development of prenatal availability of Omega-3 LCPUFA present in fish and of LCPUFA in the overall diet. Furthermore, they indicate that the beneficial effects of LCPUFA can obscure the determination of adverse effects of prenatal MeHg exposure in longitudinal observational studies.

Neurodevelopmental Effects of Maternal Nutritional Status and Exposure to Methylmercury from Eating Fish during Pregnancy

Fish contain nutrients that promote optimal brain growth and development but also contain methylmercury (MeHg) that can have toxic effects. The present study tested the hypothesis that the intake of selected nutrients in fish or measures of maternal nutritional status may represent important confounders when estimating the effects of prenatal methylmercury exposure on child development. The study took place in the Republic of Seychelles, an Indian Ocean archipelago where fish consumption is high. A longitudinal cohort study design was used. A total of 300 mothers were enrolled early in pregnancy. Nutrients considered to be important for brain development were measured during pregnancy along with prenatal MeHg exposure. The children were evaluated periodically to age 30 months. There were 229 children with complete outcome and covariate data for analysis. The primary endpoint was the Bayley Scales of Infant Development-II (BSID-II), administered at 9 and 30 months of age. Combinations of four secondary measures of infant cognition and memory were also given at 5, 9 and 25 months. Cohort mothers consumed an average of 537 g of fish (nine meals containing fish) per week. The average prenatal MeHg exposure was 5.9 ppm in maternal hair. The primary analysis examined the associations between MeHg, maternal nutritional measures and childrens scores on the BSID-II and showed an adverse association between MeHg and the mean Psychomotor Developmental Index (PDI) score at 30 months. Secondary analyses of the association between the PDI and only MeHg alone or nutritional factors alone showed only a borderline significant association between MeHg and the PDI at 30 months and no associations with nutritional factors. One experimental measure at 5 months of age was positively associated with iodine status, but not prenatal MeHg exposure. These findings suggest a possible confounding role of maternal nutrition in studies examining associations between prenatal MeHg exposures and developmental outcomes in children.

Postnatal Exposure to Methyl Mercury from Fish Consumption: a Review and New Data from the Seychelles Child Development Study

BACKGROUND Fish is an important source of nutrition worldwide. Fish contain both the neurotoxin methyl mercury (MeHg) and nutrients important for brain development. The developing brain appears to be most sensitive to MeHg toxicity and mothers who consume fish during pregnancy expose their fetus prenatally. Although brain development is most dramatic during fetal life, it continues for years postnatally and additional exposure can occur when a mother breast feeds or the child consumes fish. This raises the possibility that MeHg might influence brain development after birth and thus adversely affect childrens developmental outcomes. We reviewed postnatal MeHg exposure and the associations that have been published to determine the issues associated with it and then carried out a series of analyses involving alternative metrics of postnatal MeHg exposure in the Seychelles Child Development Study (SCDS) Main Cohort. METHODS The SCDS is a prospective longitudinal evaluation of prenatal MeHg exposure from fish consumption. The Main Cohort includes 779 subjects on whom recent postnatal exposure data were collected at the 6-, 19-, 29-, 66-, and 107-month evaluations. We examined the association of recent postnatal MeHg exposure with multiple 66- and 107-month outcomes and then used three types of alternative postnatal exposure metrics to examine their association with the childrens intelligence quotient (IQ) at 107 months of age. RESULTS Recent postnatal exposure at 107 months of age was adversely associated with four endpoints, three in females only. One alternative postnatal metric was beneficially associated with 9-year IQ in males only. CONCLUSIONS We found several associations between postnatal MeHg biomarkers and childrens developmental endpoints. However, as has been the case with prenatal MeHg exposure in the SCDS Main Cohort study, no consistent pattern of associations emerged to support a causal relationship.

High Heritability of Ambulatory Blood Pressure in Families of East African Descent

We estimated the heritability of ambulatory systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) in east African families with at least 2 hypertensive siblings and living in the Seychelles islands (Indian Ocean). The sample consisted of 314 individuals (147 men and 167 women), both normotensive and hypertensive, from 76 pedigrees (mean±SD of 4.1±2.8 persons per pedigree). After a 2-week off-treatment period, daytime and nighttime ambulatory blood pressure (BP) was monitored. Office BP was measured with a standard mercury sphygmomanometer. We estimated by maximum likelihood the age- and sex-adjusted heritabilities from the additive polygenic component of the variance of the traits allowing for the presence of other familial correlations. We also adjusted for ascertainment (ie, for the fact that 2 siblings had to be hypertensive) and examined the effect of adjusting for body mass index, 24-hour urinary excretion of sodium and potassium, plasma renin activity, and plasma aldosterone concentration. Heritability estimates (±SE) for ambulatory SBP, DBP, and PP were, respectively, 0.37±0.12/0.24±0.12/0.54±0.12 for daytime and 0.34±0.13/ 0.37±0.15/0.47±0.12 for nighttime measurements (P<0.05 for all estimates). Heritability estimates for office SBP, DBP, and PP were, respectively, 0.20±0.11, 0.05±0.09, and 0.37±0.12. Heritability estimates for SBP varied markedly according to whether participants were treated for hypertension at baseline. The present data show that ambulatory BP and PP have a high heritability in families of African descent. They also demonstrate that antihypertensive treatment and the number of BP measurements have a major influence on the heritability estimates.

Fish consumption, mercury exposure, and their associations with scholastic achievement in the Seychelles Child Development Study §

Studies of neurodevelopmental outcomes in offspring exposed to MeHg from maternal consumption of fish have primarily measured cognitive abilities. Reported associations have been subtle and in both adverse and beneficial directions. Changes in functional outcomes such as school achievement and behavior in exposed children and adolescents have not been examined. We undertook an assessment of school success of children in the Seychelles Child Development Study (SCDS) main cohort to determine if there were any associations with either prenatal or recent postnatal MeHg exposure. The primary endpoints were Seychelles nationally standardized end-of-year examinations given when the cohort children were 9 and 17 years of age. A subgroup (n=215) from the main cohort was also examined at 9 years of age using a regional achievement test called SACMEQ. Prenatal MeHg exposure was 6.8 ppm in maternal hair; recent postnatal exposure was 6.09 ppm at 9 years and 8.0 ppm at 17 years, measured in child hair. Multiple linear regression analyses showed no pattern of associations between prenatal or postnatal exposure, and either the 9- or 17-year end-of-year examination scores. For the subgroup of 215 subjects who participated in the SACMEQ test, there were significant adverse associations between examination scores and postnatal exposure, but only for males. The average postnatal exposure level in child hair for this subgroup was significantly higher than for the overall cohort. These results are consistent with our earlier studies and support the interpretation that prenatal MeHg exposure at dosages achieved by mothers consuming a diet high in fish are not associated with adverse educational measures of scholastic achievement. The adverse association of educational measures with postnatal exposure in males is intriguing, but will need to be confirmed by further studies examining factors that influence scholastic achievement.

A longitudinal analysis of prenatal exposure to methylmercury and fatty acids in the Seychelles

BACKGROUND Maternal fish consumption during pregnancy exposes the fetus simultaneously to methylmercury (MeHg) and long chain polyunsaturated fatty acids (LCPUFA). Data from the Seychelles Child Development Nutrition Study (SCDNS) showed a negative association of MeHg with child development when children were 30 months of age, only when controlling for LCPUFA. Concomitantly, n-3 LCPUFA were found to have a significant positive association only at 9 months. These findings suggest that the effects of MeHg and LCPUFA may vary with age over the first few years of life. We address this by including outcomes at two ages and adjusting for the childs age at testing. METHODS A longitudinal analysis utilizing linear mixed models was performed to assess the associations of maternal hair total mercury (THg, a biomarker for MeHg) and maternal LCPUFA with childrens Bayley Scales of Infant Development Psychomotor Developmental Index (BSID-II PDI) at 9 and 30 months of age, and to determine whether these associations change over time. Data from 228 children were included. RESULTS Maternal hair MeHg had a negative effect on BSID PDI, while maternal n-3 LCPUFA had a positive effect. These effects did not change significantly from 9 to 30 months in this analysis. CONCLUSIONS The longitudinal analysis provides increased power for estimating the relationships of prenatal MeHg and LCPUFA exposures during child development. Significant associations of these exposures in opposite directions confirm the importance of LCPUFA in development and the need to adjust for maternal nutrition when studying prenatal MeHg exposure.

Association between prenatal exposure to methylmercury and visuospatial ability at 10.7 years in the seychelles child development study

The Seychelles Child Development Study was designed to test the hypothesis that prenatal exposure to MeHg from maternal consumption of a diet high in fish is detrimental to child neurodevelopment. To date, no consistent pattern of adverse associations between prenatal exposure and childrens development has appeared. In a comprehensive review of developmental studies involving MeHg, a panel of experts recommended a more consistent use of the same endpoints across studies to facilitate comparisons. Both the SCDS and the Faeroe Islands studies administered the Bender Visual Motor Gestalt Test. However, the method of test administration and scoring used was different. We repeated the test on the SCDS Main Study children (mean age 10.7 years) using the same testing and scoring procedure reported by the Faeroe studies to obtain Copying Task and Reproduction Task scores. We found no association between prenatal MeHg exposure and Copying Task scores which was reported from the Faeroese study. However, our analysis did show a significant adverse association between MeHg and Reproduction Task scores with all the data (p=0.04), but not when the single outlier was removed (p=0.07). In a population whose exposure to MeHg is from fish consumption, we continue to find no consistent adverse association between MeHg and visual motor coordination.

CYP3A5 and ABCB1 Genes Influence Blood Pressure and Response to Treatment, and Their Effect Is Modified by Salt

The permeability–glycoprotein efflux-transporter encoded by the multidrug resistance 1 (ABCB1) gene and the cytochromes P450 3A4/5 encoded by the CYP3A4/5 genes are known to interact in the transport and metabolism of many drugs. Recent data have shown that the CYP3A5 genotypes influence blood pressure and that permeability–glycoprotein activity might influence the activity of the renin–angiotensin system. Hence, these 2 genes may contribute to blood pressure regulation in humans. We analyzed the association of variants of the ABCB1 and CYP3A5 genes with ambulatory blood pressure, plasma renin activity, plasma aldosterone, endogenous lithium clearance, and blood pressure response to treatment in 72 families (373 individuals; 55% women; mean age: 46 years) of East African descent. The ABCB1 and CYP3A5 genes interact with urinary sodium excretion in their effect on ambulatory blood pressure (daytime systolic: P=0.05; nighttime systolic and diastolic: P<0.01), suggesting a gene–gene–environment interaction. The combined action of these genes is also associated with postproximal tubular sodium reabsorption, plasma renin activity, plasma aldosterone, and with an altered blood pressure response to the angiotensin-converting enzyme inhibitor lisinopril (P<0.05). This is the first reported association of the ABCB1 gene with blood pressure in humans and demonstration that genes encoding for proteins metabolizing and transporting drugs and endogenous substrates contribute to blood pressure regulation.